A Non-invasive System for Delivering Neural Growth Factors across the Blood-Brain Barrier: A Review
A Non-invasive System for Delivering Neural Growth Factors across the Blood-Brain Barrier: A Review
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DOI：
10.1515/revneuro.1998.9.1.31
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发表时间：
1998
影响因子：
4.1
通讯作者：
A. Granholm;D. Albeck;C. Bäckman;M. Curtis;T. Ebendal;P. Friden;Michael Henry,;B. Hoffer;J. Kordower;G. Rose;S. Söderström;R. Bartus
中科院分区：
文献类型：
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作者：
A. Granholm;D. Albeck;C. Bäckman;M. Curtis;T. Ebendal;P. Friden;Michael Henry,;B. Hoffer;J. Kordower;G. Rose;S. Söderström;R. Bartus
大鼠脑室注射神经生长因子(NGF)可以减轻与年龄相关的中枢胆碱能神经元的萎缩和伴随的记忆损伤，并保护这些神经元免受各种干扰。由于神经营养因子不会大量通过血脑屏障(BBB)，因此需要开发一种非侵入性的治疗分子递送系统。我们利用由NGF共价连接到抗转铁蛋白受体抗体(OX-26)的载体系统，将具有生物活性的NGF运送到血脑屏障。该载体系统的生物活性通过体外生物测定和眼内移植进行了测试；我们能够证明，通过静脉注射OX-26-NGF结合物，发育中和老化的眼内隔移植物中的胆碱能标志物都得到了增强。在随后的实验中，老年(24个月大)Fischer 344大鼠接受了为期6周的静脉注射OX-26-NGF结合物，结果显著改善了先前受损的大鼠的空间学习能力，但扰乱了先前未受损的大鼠的学习能力。神经解剖学分析表明，OX-26-NGF偶联治疗导致最初空间学习障碍大鼠内侧隔区胆碱能细胞体积显著增加，低亲和力和高亲和力NGF受体上调。最后，OX-26-NGF能够保护纹状体胆碱能神经元免受兴奋性毒性，并保护基底前脑胆碱能神经元免受化学诱导的靶神经元丢失所致的变性。这些结果表明，转铁蛋白受体抗体递送系统在治疗神经营养物质引起的神经退行性疾病方面具有潜在的应用价值。
Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment, as well as protect these neurons against a variety of perturbations. Since neurotrophins do not pass the blood-brain barrier (BBB) in significant amounts, a non-invasive delivery system for this group of therapeutic molecules needs to be developed. We have utilized a carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. The biological activity of this carrier system was tested using in vitro bioassays and intraocular transplants; we were able to demonstrate that cholinergic markers in both developing and aged intraocular septal grafts were enhanced by intravenous delivery of the OX-26-NGF conjugate. In subsequent experiments, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate for 6 weeks, resulting in a significant improvement in spatial learning in previously impaired rats, but disrupting the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size as well as an upregulation of both low and high affinity NGF receptors in the medial septal region of rats initially impaired in spatial learning. Finally, OX-26-NGF was able to protect striatal cholinergic neurons against excitotoxicity and basal forebrain cholinergic neurons from degeneration associated with chemically-induced loss of target neurons. These results indicate the potential utility of the transferrin receptor antibody delivery system for treatment of neurodegenerative disorders with neurotrophic substances.